Since articular cartilage is composed of hyaline cartilage lacking vascular, nerve and lymph, it is considered as a tissue that has very poor regeneration ability. Various factors such as genetic factor, injury and the like promote the release of proteoglycan from articular cartilage and at the same time, collagen type 2 which is fibrotic protein specifically existing in hyaline cartilage is decomposed. By these consecutive reaction, degeneration or destruction of articular cartilage tissue progresses irreversibly. As a result, an articulation loses smooth mobility and becomes difficult to absorb an external impact, which leads to cartilage disorder. In critical condition, an articulation loses the function itself. Aging is considered as one of the causes of cartilage disorder and the number of patients is expected to increase in a future aging society.
According to these circumstances, a compound which can achieve radical remedy of cartilage disorder is demanded. In addition, since the treatment of cartilage disorder takes long period, in view of reducing burden of patients, a medicine which can be directly injected to an affected part and exhibit sustained pharmacological efficacy is demanded. As a form that can be injected to the affected part and achieve sustained release the copolymer of lactic acid and glycol acid microsphere (PLGA-MS), liposome and the complex formulation with hyaluronic acid which is a component in articulation has been reported. However, PLGA-MS and liposome have safety concerns since there is possibility 1 of causing inflammation by infiltration of phagocyte or the like. In addition, regarding prior arts, any products which are retained in articulation for sufficient period and sustain a compound release have not been marketed and thus, a sustained release formulation technique for intra-articulation injection has not been established.
On the other hand, various prostaglandin derivatives are proposed as a novel medicine for radical remedy of cartilage disorder. For example, it is reported that a compound (refer to Patent Reference 1) represented by the formula (A):
(wherein R1A is carboxy or hydroxymethyl,RA-1 is oxo, methylene or halogen atom,RA-2 is hydrogen atom, hydroxy or C1-4 alkoxy,RA-3 is hydrogen atom, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynylorC1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted by 1 to 3 substituent (s) selected from the following (1) to (5) groups:(1) halogen atom, (2) C1-4 alkoxy, (3) C3-7 cycloalkyl, (4) phenyl or (5) phenyl substituted by 1 to 3 substituent(s) selected from halogen atom, C1-4 alkyl, C1-4 alkoxyl, nitro and trifluoromethyl,nA is 0 or integer from 1 to 4,provided that (1) 5-6 position and 13-14 position are not triple bond at the same time (2) when 13-14 position is double bond, the double bond is E form, Z form or EZ mixture form is effective for cartilage injury (Patent Reference 2). In addition, it is disclosed that an implant formulation combining the compound represented by the formula (A) with hydrogel and biodegradable polymer is effective for cartilage related diseases (see Patent Reference 3).
However, in these references, there is no description or suggestion of the compound represented by formula (I) or a compound suitable for a formulation which is injectable into articular cavity.